Person: Lipsitch, Marc
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Lipsitch
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Marc
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Lipsitch, Marc
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Publication Concerns about SARS-CoV-2 evolution should not hold back efforts to expand vaccination(2021) Cobey, Sarah; Larremore, Daniel B.; Grad, Yonatan; Lipsitch, MarcWhen vaccines are in limited supply, expanding the number of people who receive some vaccine can reduce disease and mortality compared to concentrating vaccines in a subset of the population. A corollary of such dose-sparing strategies is that vaccinated individuals may have less protective immunity. Concerns have been raised that expanding the fraction of the population with partial immunity to SARS-CoV-2 could increase selection for vaccine escape variants, ultimately undermining vaccine effectiveness. We argue that although this is possible, preliminary evidence instead suggests such strategies should slow the rate of vaccine or immune escape. As long as vaccination provides some protection against escape variants, the corresponding reduction in prevalence and incidence should reduce the rate at which new variants are generated and the speed of adaptation. Because there is little evidence for efficient immune selection of SARS-CoV-2 during typical infections, these population-level effects are likely to dominate vaccine-induced evolution.Publication Modeling the Comparative Impact of Individual Quarantine vs. Active Monitoring of Contacts for the Mitigation of COVID-19(2020-03-08) Peak, Corey; Kahn, Rebecca; Grad, Yonatan; Childs, Lauren; Li, Ruoran; Lipsitch, Marc; Buckee, CarolineIndividual quarantine and active monitoring of contacts are core disease control strategies, particularly for emerging infectious diseases such as Coronavirus Disease 2019 (COVID-19). To estimate the comparative efficacy of these interventions to control COVID-19, we fit a stochastic branching model, comparing two sets of reported parameters for the dynamics of the disease. Our results suggest that individual quarantine may contain an outbreak of COVID-19 with a short serial interval (4.8 days) only in settings with high intervention performance where at least three-quarters of infected contacts are individually quarantined. However, in settings where this performance is unrealistically high and the outbreak of COVID-19 continues to grow, so too will the burden of the number of contacts traced for active monitoring or quarantine. In such circumstances where resources are prioritized for scalable interventions such as social distancing, we show active monitoring or individual quarantine of high-risk contacts can contribute synergistically to social distancing. To the extent that interventions based on contact tracing can be implemented, therefore, they can help mitigate the spread of COVID-19. Our model highlights the urgent need for more data on the serial interval and the extent of presymptomatic transmission in order to make data-driven policy decisions regarding the cost-benefit comparisons of individual quarantine vs. active monitoring of contacts.Publication Enhancing Situational Awareness to Prevent Infectious Disease Outbreaks from Becoming Catastrophic(Springer Berlin Heidelberg, 2019) Lipsitch, Marc; Santillana, MauricioCatastrophic epidemics, if they occur, will very likely start from localized and far smaller (noncatastrophic) outbreaks that grow into much greater threats. One key bulwark against this outcome is the ability of governments and the health sector more generally to make informed decisions about control measures based on accurate understanding of the current and future extent of the outbreak. Situation reporting is the activity of periodically summarizing the state of the outbreak in a (usually) public way. We delineate key classes of decisions whose quality depends on high-quality situation reporting, key quantities for which estimates are needed to inform these decisions, and the traditional and novel sources of data that can aid in estimating these quantities. We emphasize the important role of situation reports as providing public, shared planning assumptions that allow decision makers to harmonize the response while making explicit the uncertainties that underlie the scenarios outlined for planning. In this era of multiple data sources and complex factors informing the interpretation of these data sources, we describe four principles for situation reporting:1. Situation reporting should be thematic, concentrating on essential areas of evidence needed for decisions. 2. Situation reports should adduce evidence from multiple sources to address each area of evidence, along with expert assessments of key parameters. 3. Situation reports should acknowledge uncertainty and attempt to estimate its magnitude for each assessment.4. Situation reports should contain carefully curated visualizations along with text and tables.Publication Human Challenge Studies to Accelerate Coronavirus Vaccine Licensure(2020-03) Eyal, Nir; Lipsitch, Marc; Smith, Peter G.Controlled human challenge trials of SARS-CoV-2 vaccine candidates could accelerate the testing and potential rollout of efficacious vaccines. By replacing conventional Phase 3 testing of vaccine candidates, such trials may subtract many months from the licensure process, making efficacious vaccines available more quickly. Obviously, challenging volunteers with this live virus risks inducing severe disease and possibly even death. However, we argue that such studies, by accelerating vaccine evaluation, could reduce the global burden of coronavirus-related mortality and morbidity. Volunteers in such studies could autonomously authorize the risks to themselves, and their net risk could be acceptable if participants comprise healthy young adults, who are at relatively low risk of serious disease following natural infection, they have a high baseline risk of natural infection, and during the trial they receive frequent monitoring and, following any infection, the best available care.Publication Depletion-of-susceptibles bias in influenza vaccine waning studies: how to ensure robust results(Cambridge University Press, 2019-08-12) Lipsitch, Marc; Goldstein, Edward; Ray, G. Thomas; Fireman, BruceVaccine effectiveness (VE) studies are subject to biases due to depletion of at-risk persons or of highly susceptible persons at different rates from different groups (depletion-of-susceptibles bias), a problem that can also lead to biased estimates of waning effectiveness, including spurious inference of waning when none exists. An alternative study design to identify waning is to study only vaccinated persons, and compare for each day the incidence in persons with earlier or later dates of vaccination. Prior studies suggested under what conditions this alternative would yield correct estimates of waning. Here we define the depletion-of-susceptibles process formally and show mathematically that for influenza vaccine waning studies, a randomized trial or corresponding observational study that compares incidence at a specific calendar time among individuals vaccinated at different times before the influenza season begins will not be vulnerable depletion-of-susceptibles bias in its inference of waning under the null hypothesis that none exists, and will - if waning does actually occur - underestimate the extent of waning. Such a design is thus robust in the sense that a finding of waning in that inference framework reflects actual waning of vaccine-induced immunity. We recommend such a design for future studies of waning, whether observational or randomized.Publication Using predicted imports of 2019-nCoV cases to determine locations that may not be identifying all imported cases(2020-02-05) Martinez de Salazar Munoz, Pablo; Niehus, Rene; Taylor, Aimee; Buckee, Caroline; Lipsitch, MarcCases from the ongoing outbreak of atypical pneumonia caused by the 2019 novel coronavirus (2019-nCoV) exported from mainland China can lead to self-sustained outbreaks in other populations. Internationally imported cases are currently being reported in several different locations. Early detection of imported cases is critical for containment of the virus. Based on air travel volume estimates from Wuhan to international destinations and using a generalized linear regression model we identify locations which may potentially have undetected internationally imported cases.Publication Mathematical modelling for antibiotic resistance control policy: do we know enough?(Springer Science and Business Media LLC, 2019-11-29) Knight, Gwenan M.; Davies, Nicholas G.; Colijn, Caroline; Coll, Francesc; Donker, Tjibbe; Gifford, Danna R.; Glover, Rebecca E.; Jit, Mark; Klemm, Elizabeth; Lehtinen, Sonja; Lindsay, Jodi A.; Lipsitch, Marc; Llewelyn, Martin J.; Mateus, Ana L. P.; Robotham, Julie V.; Sharland, Mike; Stekel, Dov; Yakob, Laith; Atkins, Katherine E.Background Antibiotics remain the cornerstone of modern medicine. Yet there exists an inherent dilemma in their use: we are able to prevent harm by administering antibiotic treatment as necessary to both humans and animals, but we must be mindful of limiting the spread of resistance and safeguarding the efficacy of antibiotics for current and future generations. Policies that strike the right balance must be informed by a transparent rationale that relies on a robust evidence base. Main text One way to generate the evidence base needed to inform policies for managing antibiotic resistance is by using mathematical models. These models can distil the key drivers of the dynamics of resistance transmission from complex infection and evolutionary processes, as well as predict likely responses to policy change in silico. Here, we ask whether we know enough about antibiotic resistance for mathematical modelling to robustly and effectively inform policy. We consider in turn the challenges associated with capturing antibiotic resistance evolution using mathematical models, and with translating mathematical modelling evidence into policy. Conclusions We suggest that in spite of promising advances, we lack a complete understanding of key principles. From this we advocate for priority areas of future empirical and theoretical research.Publication Estimating the hospitalization burden associated with influenza and respiratory syncytial virus in New York City, 2003–2011(John Wiley & Sons, Ltd, 2015) Goldstein, Edward; Greene, Sharon K; Olson, Donald R; Hanage, William; Lipsitch, MarcBackground: Hospitalization burden associated with influenza and respiratory syncytial virus (RSV) is uncertain due to ambiguity in the inference methodologies employed for its estimation. Objectives: Utilization of a new method to quantitate the above burden. Methods: Weekly hospitalization rates for several principal diagnoses from 2003 to 2011 in New York City by age group were regressed linearly against incidence proxies for the major influenza subtypes and RSV adjusting for temporal trends and seasonal baselines. Results: Average annual rates of influenza-associated respiratory hospitalizations per 100 000 were estimated to be 129 [95% CI (79, 179)] for age <1, 36·3 (21·6, 51·4) for ages 1–4, 10·6 (7·5, 13·7) for ages 5–17, 25·6 (21·3, 29·8) for ages 18–49, 65·5 (54·0, 76·9) for ages 50–64, 125 (105, 147) for ages 65–74, and 288 (244, 331) for ages ≥75. Additionally, influenza had a significant contribution to hospitalization rates with a principal diagnosis of septicemia for ages 5–17 [0·76 (0·1, 1·4)], 18–49 [1·02 (0·3, 1·7)], 50–64 [4·0 (1·7, 6·3)], 65–74 [8·8 (2·2, 15·6)], and ≥75 [38·7 (25·7, 52·9)]. RSV had a significant contribution to the rates of respiratory hospitalizations for age <1 [1900 (1740, 2060)], ages 1–4 [117 (70, 167)], and ≥75 [175 (44, 312)] [including chronic lower respiratory disease, 90 (43, 140)] as well as pneumonia & influenza hospitalizations for ages 18–49 [6·2 (1·1, 11·3)] and circulatory hospitalizations for ages ≥75 [199 (13, 375)]. Conclusions: The high burden of RSV hospitalizations among young children and seniors age ≥75 suggests the need for additional control measures such as vaccination to mitigate the impact of annual RSV epidemics. Our estimates for influenza-associated hospitalizations provide further evidence of the burden of morbidity associated with influenza, supporting current guidelines regarding influenza vaccination and antiviral treatment.Publication Effect of Serotype on Pneumococcal Competition in a Mouse Colonization Model(American Society of Microbiology, 2015) Trzciński, Krzysztof; Li, Yuan; Weinberger, Daniel M.; Thompson, Claudette; Cordy, Derrick; Bessolo, Andrew; Malley, Richard; Lipsitch, MarcABSTRACT Competitive interactions between Streptococcus pneumoniae strains during host colonization could influence the serotype distribution in nasopharyngeal carriage and pneumococcal disease. We evaluated the competitive fitness of strains of serotypes 6B, 14, 19A, 19F, 23F, and 35B in a mouse model of multiserotype carriage. Isogenic variants were constructed using clinical strains as the capsule gene donors. Animals were intranasally inoculated with a mixture of up to six pneumococcal strains of different serotypes, with separate experiments involving either clinical isolates or isogenic capsule-switch variants of clinical strain TIGR4. Upper-respiratory-tract samples were repeatedly collected from animals in order to monitor changes in the serotype ratios using quantitative PCR. A reproducible hierarchy of capsular types developed in the airways of mice inoculated with multiple strains. Serotype ranks in this hierarchy were similar among pneumococcal strains of different genetic backgrounds in different strains of mice and were not altered when tested under a range of host conditions. This rank correlated with the measure of the metabolic cost of capsule synthesis and in vitro measure of pneumococcal cell surface charge, both parameters considered to be predictors of serotype-specific fitness in carriage. This study demonstrates the presence of a robust competitive hierarchy of pneumococcal serotypes in vivo that is driven mainly, but not exclusively, by the capsule itself.Publication Antibiotics in agriculture and the risk to human health: how worried should we be?(Blackwell Publishing Ltd, 2015) Chang, Rose; Wang, Weike; Regev-Yochay, Gili; Lipsitch, Marc; Hanage, WilliamThe use of antibiotics in agriculture is routinely described as a major contributor to the clinical problem of resistant disease in human medicine. While a link is plausible, there are no data conclusively showing the magnitude of the threat emerging from agriculture. Here, we define the potential mechanisms by which agricultural antibiotic use could lead to human disease and use case studies to critically assess the potential risk from each. The three mechanisms considered are as follows 1: direct infection with resistant bacteria from an animal source, 2: breaches in the species barrier followed by sustained transmission in humans of resistant strains arising in livestock, and 3: transfer of resistance genes from agriculture into human pathogens. Of these, mechanism 1 is the most readily estimated, while significant is small in comparison with the overall burden of resistant disease. Several cases of mechanism 2 are known, and we discuss the likely livestock origins of resistant clones of Staphylococcus aureus and Enterococcus faecium, but while it is easy to show relatedness the direction of transmission is hard to assess in robust fashion. More difficult yet to study is the contribution of mechanism 3, which may be the most important of all.